The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 3 956-959
Copyright © 1999 by The Endocrine Society
Selective Lack of Growth Hormone (GH) Response to the GH-Releasing Peptide Hexarelin in Patients with GH-Releasing Hormone Receptor Deficiency1
Hiralal G. Maheshwari,
Asad Rahim,
Stephen M. Shalet and
Gerhard Baumann
Center for Endocrinology, Metabolism, and Molecular Medicine,
Department of Medicine, Northwestern University Medical School (H.G.M.,
G.B.), Chicago, Illinois 60611; and the Department of Endocrinology,
Christie Hospital (A.R., S.M.S.), Withington, Manchester, United
Kingdom M20 4BX
Address all correspondence and requests for reprints to: G. Baumann, M.D., Northwestern University Medical School, 303 East Chicago Avenue, Chicago, Illinois 60611. E-mail: gbaumann{at}nwu.edu
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Abstract
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The mechanism of the synergistic relationship between GH-releasing
peptide (GHRP) and GHRH with respect to GH secretion is poorly
understood. We report the response to hexarelin, a potent GHRP, in
patients affected with a homozygous mutation in the GHRH receptor gene,
with consequent GHRH resistance and GH-deficient dwarfism. This newly
described syndrome is the human homolog of the little
(lit/lit) mouse. Intravenous administration of hexarelin
(2 µg/kg) to four male adult patients (dwarfs of Sindh) resulted in a
complete lack of elevation in plasma GH levels (<1 ng/mL), an at least
50- to 100-fold deviation from the normal response. In contrast, plasma
PRL, ACTH, and cortisol levels rose in a normal manner in response to
hexarelin. We conclude that an intact GHRH signaling system is critical
for GHRPs to exert their effect on GH release, but that the GHRH system
is not necessary for the effect of GHRP on PRL and ACTH secretion.
Hexarelin (and probably other GHRPs) are not effective agents for the
treatment of patients with GHRH resistance due to GHRH receptor
deficiency.
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Introduction
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THE GH-RELEASING peptides (GHRP) are a
class of small peptides that stimulate GH and, to a lesser degree, PRL
and ACTH secretion from the pituitary gland (1, 2, 3). They interact with
a recently cloned specific receptor that is expressed in the
hypothalamus and pituitary (4). Orally active nonpeptide GHRP mimetics
that bind to the same receptor and act as GH/PRL/ACTH secretagogues
have been developed (3). The GHRPs are believed to represent analogs of
a still unknown endogenous ligand for the GHRP receptor. This putative
ligand is thought to participate in the regulation of GH secretion, in
conjunction with GHRH and somatostatin. GHRPs synergize with GHRH in
releasing GH by an unknown, primarily hypothalamic mechanism;
coadministration of GHRP with GHRH in vivo results in a
large potentiation of the GHRH effect (5, 6). The effect of GHRP on
GHRH action at the pituitary level is smaller and additive rather than
synergistic (7, 8). Despite efforts at elucidating the GHRH-GHRP
relationship, the nature of their interaction remains poorly
understood, partly because of the difficulty in isolating the effects
of GHRH, somatostatin, and GHRP in vivo.
To shed further light on the cross-talk between GHRH and GHRP, we
studied individuals with a unique new syndrome of genetic GHRH receptor
(GHRH-R) deficiency (dwarfism of Sindh) (9, 10) to determine the
efficacy of GHRP in elaborating GH, PRL, and ACTH release in the
absence of GHRH signaling. Patients affected by this mutation in the
GHRH-R are profoundly GH deficient because of GHRH resistance at the
pituitary level (9, 10, 11, 12). A practical aim of the study was to determine
whether GHRP or its oral analogs may represent a therapeutic modality
for the affected patients who live in a rural area of Pakistan where
medical services are limited. Hexarelin, the GHRP used in this study,
is a potent GHRP whose effects in normal human subjects are well
characterized (13).
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Subjects and Methods
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Four adult males with a homozygous GHRH-R defect, aged 23, 28,
28, and 30 yr, participated in the study. Their genetic, physical, and
endocrine characteristics have been described in detail previously (9, 10). None had been treated with GH or any other form of endocrine
therapy. They traveled to Manchester, UK, and after acclimatization for
2 days, underwent standard testing with hexarelin (Pharmacia & Upjohn, Stockholm, Sweden). The study protocol was
approved by the Northwestern University institutional review board and
the South Manchester medical research ethics committee. After giving
informed consent, the patients had an iv cannula inserted at 0800
h, and baseline fasting blood samples were drawn at 0900 and 0915
h. Hexarelin (2 µg/kg) was administered iv at 0915 h, and blood
was drawn 15, 30, 45, 60, 90, and 120 min after the injection. No
adverse effects were observed, except transient mild flushing and a
feeling of hunger in two subjects.
Blood was immediately cooled on ice and processed within 30 min of
venipuncture. Plasma was frozen immediately until assayed. GH was
measured by an in-house two-site immunoradiometric assay (14), with a
limit of detection of 0.35 ng/mL. PRL and cortisol were measured by
commercial two-site immunochemiluminescent assays (Chiron Diagnostics,
East Walpole, MA), and ACTH was determined by a commercial RIA kit
(Diagnostic Systems Laboratories, Inc., Webster, TX) with
a detection limit of 25 pg/mL.
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Results
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The responses of plasma GH, PRL, ACTH, and cortisol to hexarelin
are shown in Fig. 1
. The GH response was
essentially absent: two subjects showed no rise in GH above the
detection threshold (<0.35 ng/mL), and in two others there was a
biologically insignificant rise to a peak of about 1 ng/mL. The normal
peak value response in subjects of the same age and sex is
approximately 70 ng/mL (13, 15, 16, 17, 18, 19).
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Figure 1. Responses of plasma GH, PRL, ACTH, and
cortisol to hexarelin (2 µg/kg, iv) in four adult men affected with
GHRH-R deficiency due to a homozygous nonsense mutation in the GHRH-R
gene. The arrows indicate the injection of hexarelin at
time zero.
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In contrast, the PRL, ACTH, and cortisol responses to hexarelin were
comparable to those in normal subjects (13, 17, 18, 19).
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Discussion
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The present study demonstrates that in humans, an intact GHRH
signaling system is an absolute requirement for GH secretion in
response to hexarelin, and hence probably other GHRPs. It also clearly
shows that GHRH signaling is not necessary for PRL or ACTH release
induced by GHRP. The latter observation is consistent with the absence
of synergy between GHRH and GHRP with respect to PRL or ACTH secretion
(20). The mechanism for PRL release by GHRP is largely unknown,
although direct somatomammotroph stimulation has been implicated (3, 21). ACTH secretion is thought to be effected via hypothalamic
activation of CRH and/or vasopressin release by GHRP (22, 23). Neither
of these mechanisms appears to be influenced by GHRH. Conversely, the
dependence of GHRP-induced GH secretion on an intact GHRH-R is
congruent with reports that treatment with GHRH antagonist or anti-GHRH
antibody attenuates the GH response to GHRP (7, 24, 25, 26). This
dependence on an intact GHRH system is demonstrated with particular
clarity in our patients because of the severity of the underlying
germline nonsense mutation in the GHRH-R gene, which makes the
existence of even a partially functional receptor virtually impossible
(9, 10, 11, 12). The lack of a GH response to hexarelin in human GHRH-R
deficiency is also in agreement with a report that the little
(lit/lit) mouse, which bears an inactivating missense
mutation in the GHRH-R (27, 28), does not secrete GH in response to
GHRP-6 (29).
One theoretical reason for nonresponsivity to GHRP could be a
deficiency in GHRP-receptors. We have no direct data on GHRP receptor
expression or function in our patients, but there is no a
priori reason to postulate a second lesion beyond GHRH-R
deficiency. Whether GHRH action is necessary for normal GHRP receptor
expression is unknown. The fact that hexarelin induced PRL, ACTH, and
cortisol responses argues against a defect in the GHRP-receptor.
Furthermore, the little mouse has been shown to respond to GHRP with
c-fos expression in the arcuate nucleus similar to that in
normal rodents, implying a functional GHRP receptor at least in the
central nervous system (30). Thus, it appears unlikely that a GHRP
receptor defect is responsible for the lack of a GH response to
hexarelin.
Another potential explanation for the absence of a GH response is
pituitary (somatotroph) hypoplasia. GHRH is an important factor for
somatotroph development and GH synthesis, and the number of
somatotrophs and the GH content per somatotroph are reduced in the
little mouse (28, 31). Similarly, the pituitary glands of our and other
patients with the GHRH-R deficiency are small (12) (Baumann, G., H. G.
Maheshwari, E. J. Russell; unpublished). Therefore, the
possibility of insufficient GH stores to yield a detectable increase in
serum GH despite a normal GHRP response must be considered. Although
this possibility may be contributory, it is unlikely to be the full
explanation. The little mouse pituitary contains about 25% of the
normal complement of somatotrophs and 4–8% of the GH content of a
normal pituitary (32, 33). Translated to a GHRH-R-deficient human
pituitary, this would represent between 0.5–1 mg stored GH. A typical
GHRP response from such a reduced GH pool in a dwarfed, 30-kg subject
can be estimated to yield a peak plasma value of 5–10 ng/mL, a value
far greater than that which we observed. Furthermore, agents acting
distal to the GHRH-R, such as forskolin, cholera toxin, or cAMP, effect
an exuberant GH release from little mouse pituitary cell cultures
in vitro (34). Thus, we believe that the absence of a GH
response is principally due to the lack of a functional GHRH signaling
system.
The ACTH responses in our patients are small and somewhat
erratic, yet the cortisol response is very robust. The magnitude of the
mean ACTH response at 15 min (an increment of 11 pg/mL) is similar to
or slightly less than that in other reports (16, 17, 18), but the baseline
ACTH levels are high, and evidence for activation of ACTH secretion is
present throughout the test period. We attribute this to some
apprehension of these patients transplanted into a foreign environment
and undergoing intravenous testing. Of interest, in one study in rats,
the ACTH response to GHRP was inversely related to the baseline ACTH
level (23). The relatively small ACTH response in our patients may
similarly reflect their high initial plasma ACTH concentration.
It follows from our results that hexarelin, and probably other GHRPs
and GHRP mimetics, are not efficacious as a treatment for dwarfism in
patients with GHRH-R deficiency. Rather, such patients will have to
rely on treatment with GH. There is evidence that GH therapy is
effective in this syndrome with respect to both short term biochemical
end points (9, 10) and long term growth (11, 12).
In summary, the present study shows that hexarelin is unable to release
GH in patients with GHRH-R deficiency, but PRL, ACTH, and cortisol
responses to hexarelin are normal. These findings underscore the
synergy between GHRH and GHRP and the absolute requirement of a
functional GHRH system for GHRPs to function as GH secretagogues. In
contrast, the GHRH system is apparently not involved, or at least is
not crucial, for PRL and ACTH secretion in response to GHRP. GHRP is
not a therapeutic option in overcoming genetic GHRH resistance.
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Acknowledgments
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We thank Drs. D. Linkie, B. Lippe, M. Boghen, and R. Gunnarsson
of Pharmacia & Upjohn for their help in making this study
possible. The assistance of Christine Smith is gratefully
acknowledged.
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Footnotes
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1 This work was supported by a travel grant from Pharmacia & Upjohn. 
Received October 28, 1998.
Revised December 4, 1998.
Accepted December 8, 1998.
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Top
Abstract
Introduction
